Saladin Anatomy and Physiology The Unity of Form and Function Episode 11 doc

Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
Companies, 2003
Chapter 18
Chapter 18 The Circulatory System: Blood 691
You might wonder why human hemoglobin must be contained in RBCs.
The main reason is osmotic. Remember that the osmolarity of blood
depends on the number of particles in solution. A “particle,” for this
purpose, can be a sodium ion, an albumin molecule, or a whole cell. If
all the hemoglobin contained in the RBCs were free in the plasma, it
would drastically increase blood osmolarity, since each RBC contains
about 280 million molecules of hemoglobin. The circulatory system
would become enormously congested with fluid, and circulation would
be severely impaired. The blood simply could not contain that much free
hemoglobin and support life. On the other hand, if it contained a safe
level of free hemoglobin, it could not transport enough oxygen to sup-
port the high metabolic demand of the human body. By having our
hemoglobin packaged in RBCs, we are able to have much more of it and
hence to have more efficient gas transport and more active metabolism.
Quantities of Erythrocytes
and Hemoglobin
The RBC count and hemoglobin concentration are impor-
tant clinical data because they determine the amount of
oxygen the blood can carry. Three of the most common

measurements are hematocrit, hemoglobin concentration,
and RBC count. The hematocrit
11
(packed cell volume,
PCV) is the percentage of whole blood volume composed
of RBCs (see fig. 18.2). In men, it normally ranges between
42% and 52%; in women, between 37% and 48%. The
hemoglobin concentration of whole blood is normally 13
to 18 g/dL in men and 12 to 16 g/dL in women. The RBC
count is normally 4.6 to 6.2 million RBCs/␮L in men and
4.2 to 5.4 million/␮L in women. This is often expressed as
cells per cubic millimeter (mm
3
); 1 ␮L ϭ 1 mm
3
.
Notice that these values tend to be lower in women
than in men. There are three physiological reasons for this:
(1) androgens stimulate RBC production, and men have
higher androgen levels than women; (2) women of repro-
ductive age have periodic menstrual losses; and (3) the
hematocrit is inversely proportional to percent body fat,
which is higher in women than in men. In men, the blood
also clots faster and the skin has fewer blood vessels than
in women. Such differences are not limited to humans.
From the evolutionary standpoint, the adaptive value of
these differences may lie in the fact that male animals fight
more than females and suffer more injuries. The traits
described here may serve to minimize or compensate for
their blood loss.

Think About It
Explain why the hemoglobin concentration could
appear deceptively high in a patient who is dehydrated.
Erythrocyte Death and Disposal
Circulating erythrocytes live for about 120 days. The life
of an RBC is summarized in figure 18.11. As an RBC ages
and its membrane proteins (especially spectrin) deterio-
rate, the membrane grows increasingly fragile. Without a
nucleus or ribosomes, an RBC cannot synthesize new
spectrin. Many RBCs die in the spleen, which has been
called the “erythrocyte graveyard.” The spleen has chan-
nels as narrow as 3 ␮m that severely test the ability of old,
fragile RBCs to squeeze through the organ. Old cells
become trapped, broken up, and destroyed. An enlarged
and tender spleen may indicate diseases in which RBCs
are rapidly breaking down.
11
hemato ϭ blood ϩ crit ϭ to separate
Erythropoiesis in
red bone marrow
Erythrocytes
circulate for 120 days
Expired erythrocytes
break up in liver and spleen
Small intestine
Cell fragments
phagocytized
Globin
Hemoglobin
degraded

Hydrolyzed to free
amino acids
Heme
Iron
Biliverdin
Bilirubin
Bile
Feces
Storage Reuse
Loss by
menstruation,
injury, etc.
Nutrient
absorption
Amino acids
Iron
Folic acid
Vitamin B
12
Figure 18.11 The Life and Death of Erythrocytes. Note
especially the stages of hemoglobin breakdown and disposal.
Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
Companies, 2003

Chapter 18
Table 18.5 outlines the process of disposing of old
erythrocytes and hemoglobin. Hemolysis
12
(he-MOLL-ih-
sis), the rupture of RBCs, releases hemoglobin and leaves
empty plasma membranes. The membrane fragments are
easily digested by macrophages in the liver and spleen, but
hemoglobin disposal is a bit more complicated. It must be
disposed of efficiently, however, or it can block kidney
tubules and cause renal failure. Macrophages begin the dis-
posal process by separating the heme from the globin. They
hydrolyze the globin into free amino acids, which become
part of the body’s general pool of amino acids available for
protein synthesis or energy-releasing catabolism.
Disposing of the heme is another matter. First, the
macrophage removes the iron and releases it into the
blood, where it combines with transferrin and is used or
stored in the same way as dietary iron. The macrophage
converts the rest of the heme into a greenish pigment
called biliverdin
13
(BIL-ih-VUR-din), then further con-
verts most of this to a yellow-green pigment called biliru-
bin.
14
Bilirubin is released by the macrophages and binds
to albumin in the blood plasma. The liver removes biliru-
bin from the albumin and secretes it into the bile, to which
it imparts a dark green color as the bile becomes concen-

trated in the gallbladder. Biliverdin and bilirubin are col-
lectively known as bile pigments. The gallbladder dis-
charges the bile into the small intestine, where bacteria
convert bilirubin to urobilinogen, responsible for the
brown color of the feces. Another hemoglobin breakdown
pigment, urochrome, produces the yellow color of urine.
A high level of bilirubin in the blood causes jaundice, a
yellowish cast in light-colored skin and the whites of eyes.
Jaundice may be a sign of rapid hemolysis or a liver dis-
ease or bile duct obstruction that interferes with bilirubin
disposal.
Erythrocyte Disorders
Any imbalance between the rates of erythropoiesis and
RBC destruction may produce an excess or deficiency of
red cells. An RBC excess is called polycythemia
15
(POL-
ee-sy-THEE-me-uh), and a deficiency of either RBCs or
hemoglobin is called anemia.
16
Polycythemia
Primary polycythemia (polycythemia vera) is due to cancer
of the erythropoietic line of the red bone marrow. It can
result in an RBC count as high as 11 million RBCs/␮L and
a hematocrit as high as 80%. Polycythemia from all other
causes, called secondary polycythemia, is characterized by
RBC counts as high as 6 to 8 million RBCs/␮L. It can result
from dehydration because water is lost from the blood-
stream while erythrocytes remain and become abnormally
concentrated. More often, it is caused by smoking, air pol-

lution, emphysema, high altitude, strenuous physical con-
ditioning, or other factors that create a state of hypoxemia
and stimulate erythropoietin secretion.
The principal dangers of polycythemia are increased
blood volume, pressure, and viscosity. Blood volume can
double in primary polycythemia and cause the circulatory
system to become tremendously engorged. Blood viscosity
may rise to three times normal. Circulation is poor, the
capillaries are clogged with viscous blood, and the heart is
dangerously strained. Chronic (long-term) polycythemia
can lead to embolism, stroke, or heart failure. The deadly
consequences of emphysema and some other lung dis-
eases are due in part to polycythemia.
Anemia
The causes of anemia fall into three categories: (1) inade-
quate erythropoiesis or hemoglobin synthesis, (2) hemor-
rhagic anemia from bleeding, and (3) hemolytic anemia
from RBC destruction. Table 18.6 gives specific examples
and causes for each category. We give special attention to
692
Part Four Regulation and Maintenance
12
hemo ϭ blood ϩ lysis ϭ splitting, breakdown
13
bili ϭ bile ϩ verd ϭ green ϩ in ϭ substance
14
bili ϭ bile ϩ rub ϭ red ϩ in ϭ substance
Table 18.5 The Fate of Expired
Erythrocytes and Hemoglobin
1. RBCs lose elasticity with age

2. RBCs break down while squeezing through blood capillaries and
sinusoids
3. Cell fragments are phagocytized by macrophages in the spleen and
liver
4. Hemoglobin decomposes into:
Globin portion—hydrolyzed to amino acids, which can be reused
Heme portion—further decomposed into:
Iron
1. Transported by albumin to bone marrow and liver
2. Some used in bone marrow to make new hemoglobin
3. Excess stored in liver as ferritin
Biliverdin
1. Converted to bilirubin and bound to albumin
2. Removed by liver and secreted in bile
3. Stored and concentrated in gallbladder
4. Discharged into small intestine
5. Converted by intestinal bacteria to urobilinogen
6. Excreted in feces
15
poly ϭ many ϩ cyt ϭ cell ϩ hem ϭ blood ϩ ia ϭ condition
16
an ϭ without ϩ em ϭ blood ϩ ia ϭ condition
Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill

Companies, 2003
Chapter 18
Chapter 18 The Circulatory System: Blood 693
the deficiencies of erythropoiesis and some forms of
hemolytic anemia.
Anemia often results from kidney failure, because
RBC production depends on the hormone erythropoietin
(EPO), which is produced mainly by the kidneys. Erythro-
poiesis also declines with age, simply because the kidneys
atrophy with age and produce less and less EPO as we get
older. Compounding this problem, elderly people tend to
get less exercise and to eat less well, and both of these fac-
tors reduce erythropoiesis.
Nutritional anemia results from a dietary deficiency
of any of the requirements for erythropoiesis discussed
earlier. Its most common form is iron-deficiency anemia.
Pernicious anemia can result from a deficiency of vitamin
B
12
, but this vitamin is so abundant in meat that a B
12
defi-
ciency is rare except in strict vegetarians. More often, it
occurs when glands of the stomach fail to produce a sub-
stance called intrinsic factor that the small intestine needs
to absorb vitamin B
12
. This becomes more common in old
age because of atrophy of the stomach. Pernicious anemia
can also be hereditary. It is treatable with vitamin B

12
injections; oral B
12
would be useless because the digestive
tract cannot absorb it without intrinsic factor.
Hypoplastic
17
anemia is caused by a decline in eryth-
ropoiesis, whereas the complete failure or destruction of
the myeloid tissue produces aplastic anemia, a complete
cessation of erythropoiesis. Aplastic anemia leads to
grotesque tissue necrosis and blackening of the skin. Most
victims die within a year. About half of all cases are of
unknown or hereditary cause, especially in adolescents
and young adults. Other causes are given in table 18.6.
Anemia has three potential consequences:
1. The tissues suffer hypoxia (oxygen deprivation).
The individual is lethargic and becomes short of
breath upon physical exertion. The skin is pallid
because of the deficiency of hemoglobin. Severe
anemic hypoxia can cause life-threatening necrosis
of brain, heart, and kidney tissues.
2. Blood osmolarity is reduced. More fluid is thus
transferred from the bloodstream to the intercellular
spaces, resulting in edema.
3. Blood viscosity is reduced. Because the blood puts
up so little resistance to flow, the heart beats faster
than normal and cardiac failure may ensue. Blood
pressure also drops because of the reduced volume
and viscosity.

Sickle-Cell Disease
Sickle-cell disease and thalassemia (see table 18.10) are
hereditary hemoglobin defects that occur mostly among
people of African and Mediterranean descent, respectively.
About 1.3% of African Americans have sickle-cell dis-
ease. This disorder is caused by a recessive allele that
modifies the structure of hemoglobin. Sickle-cell hemo-
globin (HbS) differs from normal HbA only in the sixth
amino acid of the ␤ chain, where HbA has glutamic acid
and HbS has valine. People who are homozygous for HbS
exhibit sickle-cell disease. People who are heterozygous
for it—about 8.3% of African Americans—have sickle-cell
trait but rarely have severe symptoms. However, if two
carriers reproduce, their children each have a 25% chance
of being homozygous and having the disease.
Without treatment, a child with sickle-cell disease
has little chance of living to age 2, but even with the best
available treatment, few victims live to the age of 50. HbS
does not bind oxygen very well. At low oxygen concentra-
tions, it becomes deoxygenated, polymerizes, and forms a
gel that causes the erythrocytes to become elongated and
pointed at the ends (fig. 18.12), hence the name of the dis-
ease. Sickled erythrocytes are sticky; they agglutinate
18
(clump together) and block small blood vessels, causing
intense pain in oxygen-starved tissues. Blockage of the
Table 18.6 Types and Causes of Anemia
Anemia Due to Inadequate Erythropoiesis
Inadequate nutrition
Iron-deficiency anemia

Folic acid, vitamin B
12
, or vitamin C deficiency
Pernicious anemia (deficiency of intrinsic factor)
Renal failure (reduced erythropoietin secretion)
Old age
Renal atrophy (reduced erythropoietin secretion)
Nutritional deficiencies
Insufficient exercise
Destruction of myeloid tissue (hypoplastic and aplastic anemia)
Radiation exposure
Viral infection
Autoimmune disease
Some drugs and poisons (arsenic, mustard gas, benzene, etc.)
Hemorrhagic Anemia, Due to Excessive Bleeding
Trauma, hemophilia, menstruation, ulcer, ruptured aneurysm, etc.
Hemolytic Anemia, Due to Erythrocyte Destruction
Mushroom toxins, snake and spider venoms
Some drug reactions (such as penicillin allergy)
Malaria (invasion and destruction of RBCs by certain parasites)
Sickle-cell disease and thalassemia (hereditary hemoglobin defects)
Hemolytic disease of the newborn (mother-fetus Rh mismatch)
17
hypo ϭ below normal ϩ plas ϭ formation ϩ tic ϭ pertaining to
18
ag ϭ together ϩ glutin ϭ glue
Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition

18. The Circulatory System:
Blood
Text
© The McGraw−Hill
Companies, 2003
Chapter 18
circulation can also lead to kidney or heart failure, stroke,
rheumatism, or paralysis. Hemolysis of the fragile cells
causes anemia and hypoxemia, which triggers further
sickling in a deadly positive feedback loop. Chronic
hypoxemia also causes fatigue, weakness, mental defi-
ciency, and deterioration of the heart and other organs. In
a futile effort to counteract the hypoxemia, the hemopoi-
etic tissues become so active that bones of the cranium and
elsewhere become enlarged and misshapen. The spleen
reverts to a hemopoietic role, while also disposing of dead
RBCs, and becomes enlarged and fibrous. Sickle-cell dis-
ease is a prime example of pleiotropy—the occurrence of
multiple phenotypic effects from a change in a single gene
(see p. 148).
Why does sickle-cell disease exist? In Africa, where
it originated, vast numbers of people die of malaria.
Malaria is caused by a parasite that invades the RBCs and
feeds on hemoglobin. Sickle-cell hemoglobin, HbS, is
indigestible to malaria parasites, and people heterozygous
for sickle-cell disease are resistant to malaria. The lives
saved by this gene outnumber the deaths of homozygous
individuals, so the gene persists in the population.
Before You Go On
Answer the following questions to test your understanding of the

preceding section:
13. Describe the shape, size, and contents of an erythrocyte, and
explain how it acquires its unusual shape.
14. What is the function of hemoglobin? What are its protein and
nonprotein moieties called?
15. What happens to each of these moieties when old erythrocytes
break up?
16. What is the body’s primary mechanism for correcting
hypoxemia? How does this illustrate homeostasis?
17. What are the three primary causes or categories of anemia?
What are its three primary consequences?
Blood Types
Objectives
When you have completed this section, you should be able to
• explain what determines a person’s ABO and Rh blood types
and how this relates to transfusion compatibility;
• describe the effect of an incompatibility between mother and
fetus in Rh blood type; and
• list some blood groups other than ABO and Rh and explain
how they may be useful.
Blood types and transfusion compatibility are a matter of
interactions between plasma proteins and erythrocytes.
Ancient Greek physicians attempted to transfuse blood
from one person to another by squeezing it from a pig’s
bladder through a porcupine quill into the recipient’s
vein. While some patients benefited from the procedure, it
was fatal to others. The reason some people have compat-
ible blood and some do not remained obscure until 1900,
when Karl Landsteiner discovered blood types A, B, and
O—a discovery that won him a Nobel Prize in 1930; type

AB was discovered later. World War II stimulated great
improvements in transfusions, blood banking, and blood
substitutes (see insight 18.3).
Insight 18.3 Medical History
Charles Drew—Blood Banking Pioneer
Charles Drew (fig. 18.13) was a scientist who lived and died in the arms
of bitter irony. After receiving his M.D. from McGill University of Mon-
treal in 1933, Drew became the first black person to pursue the
advanced degree of Doctor of Science in Medicine, for which he stud-
ied transfusion and blood-banking procedures at Columbia University.
He became the director of a new blood bank at Columbia Presbyter-
ian Hospital in 1939 and organized numerous blood banks during
World War II.
Drew saved countless lives by convincing physicians to use plasma
rather than whole blood for battlefield and other emergency transfu-
sions. Whole blood could be stored for only a week and given only to
694 Part Four Regulation and Maintenance
Figure 18.12 Blood of a Person with Sickle-Cell Disease.
Note the deformed, pointed erythrocyte.
Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
Companies, 2003
Chapter 18
Chapter 18 The Circulatory System: Blood 695

recipients with compatible blood types. Plasma could be stored longer
and was less likely to cause transfusion reactions.
When the U.S. War Department issued a directive forbidding the
mixing of Caucasian and Negro blood in military blood banks, Drew
denounced the order and resigned his position. He became a professor
of surgery at Howard University in Washington, D.C., and later chief of
staff at Freedmen’s Hospital. He was a mentor for numerous young
black physicians and campaigned to get them accepted into the med-
ical community. The American Medical Association, however, firmly
refused to admit black members, even Drew himself.
Late one night in 1950, Drew and three colleagues set out to vol-
unteer their medical services to an annual free clinic in Tuskegee,
Alabama. Drew fell asleep at the wheel and was critically injured in the
resulting accident. Doctors at the nearest hospital administered blood
and attempted unsuccessfully to revive him. For all the lives he saved
through his pioneering work in blood transfusion, Drew himself bled to
death at the age of 45.
All cells have an inherited combination of proteins,
glycoproteins, and glycolipids on their surfaces. These
function as antigens that enable our immune system to
distinguish our own cells from foreign invaders. Part of
the immune response is the production of ␥ globulins
called antibodies to combat the invader. In blood typing,
the antigens of RBC surfaces are also called agglutinogens
(ah-glue-TIN-oh-jens) because they are partially responsi-
ble for RBC agglutination in mismatched transfusions. The
plasma antibodies that react against them are also called
agglutinins (ah-GLUE-tih-nins).
The ABO Group
Blood types A, B, AB, and O form the ABO blood group

(table 18.7). Your ABO blood type is determined by the
hereditary presence or absence of antigens A and B on your
RBCs. The genetic determination of blood types is explained
on page 148. The antigens are glycoproteins and glyco-
lipids—membrane proteins and phospholipids with short
carbohydrate chains bonded to them. Figure 18.14 shows
how these carbohydrates determine the ABO blood types.
Think About It
Suppose you could develop an enzyme that
selectively split N-acetylgalactosamine off the
glycolipid of type A blood cells (fig. 18.14). What
would be the potential benefit of this product to
blood banking and transfusion?
The antibodies of the ABO group begin to appear in
the plasma 2 to 8 months after birth. They reach their max-
imum concentrations between 8 and 10 years of age and
then slowly decline for the rest of one’s life. They are pro-
duced mainly in response to the bacteria that inhabit our
intestines, but they cross-react with RBC antigens and are
therefore best known for their significance in transfusions.
Figure 18.13 Charles Drew (1904–50).
Type O Type B
Type A
Type AB
Galactose
Fucose
N-acetylgalactosamine
Key
Figure 18.14 Chemical Basis of the ABO Blood Types. The
terminal carbohydrates of the antigenic glycolipids are shown. All of

them end with galactose and fucose (not to be confused with fructose).
In type A, the galactose also has an N-acetylgalactosamine added to it; in
type B, it has another galactose; and in type AB, both of these chain
types are present.
Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
Companies, 2003
Chapter 18
AB antibodies react against any AB antigen except
those on one’s own RBCs. The antibody that reacts against
antigen A is called ␣ agglutinin, or anti-A; it is present in
the plasma of people with type O or type B blood—that is,
anyone who does not possess antigen A. The antibody that
reacts against antigen B is ␤ agglutinin, or anti-B, and is
present in type O and type A individuals—those who do
not possess antigen B. Each antibody molecule has 10
binding sites where it can attach to either an A or B anti-
gen. An antibody can therefore attach to several RBCs at
once and bind them together (fig. 18.15). Agglutination is
the clumping of RBCs bound together by antibodies.
A person’s ABO blood type can be determined by
placing one drop of blood in a pool of anti-A serum and
another drop in a pool of anti-B serum. Blood type AB
exhibits conspicuous agglutination in both antisera; type

A or B agglutinates only in the corresponding antiserum;
and type O does not agglutinate in either one (fig. 18.16).
Type O blood is the most common and AB is the
rarest in the United States. Percentages differ from one
region of the world to another and among ethnic groups
because people tend to marry within their locality and eth-
nic group and perpetuate statistical variations particular
to that group.
In giving transfusions, it is imperative that the
donor’s RBCs not agglutinate as they enter the recipient’s
bloodstream. For example, if type B blood were transfused
into a type A recipient, the recipient’s anti-B antibodies
would immediately agglutinate the donor’s RBCs (fig.
18.17). A mismatched transfusion causes a transfusion
reaction—the agglutinated RBCs block small blood ves-
sels, hemolyze, and release their hemoglobin over the next
few hours to days. Free hemoglobin can block the kidney
tubules and cause death from acute renal failure within a
week or so. For this reason, a person with type A (anti-B)
blood must never be given a transfusion of type B or AB
blood. A person with type B (anti-A) must never receive
type A or AB blood. Type O (anti-A and anti-B) individu-
als cannot safely receive type A, B, or AB blood.
Type AB is sometimes called the universal recipient
because this blood type lacks both anti-A and anti-B anti-
bodies; thus, it will not agglutinate donor RBCs of any
ABO type. However, this overlooks the fact that the
donor’s plasma can agglutinate the recipient’s RBCs if it
contains anti-A, anti-B, or both. For similar reasons, type
O is sometimes called the universal donor. The plasma of

a type O donor, however, can agglutinate the RBCs of a
type A, B, or AB recipient. There are procedures for reduc-
696
Part Four Regulation and Maintenance
Table 18.7 The ABO Blood Group
ABO Blood Type
Type O Type A Type B Type AB
Possible Genotypes ii I
A
I
A
, I
A
iI
B
I
B
, I
B
iI
A
I
B
RBC Antigen None A B A,B
Plasma Antibody Anti-A, anti-B Anti-B Anti-A None
Compatible Donor RBCs O O,A O,B O,A,B,AB
Incompatible Donor RBCs A, B, AB B, AB A, AB None
Frequency in U.S. Population
White 45% 40% 11% 4%
Black 49% 27% 20% 4%

Hispanic 63% 14% 20% 3%
Japanese 31% 38% 22% 9%
Native American 79% 16% 4% Ͻ1%
Antibodies
(agglutinins)
Figure 18.15 Agglutination of RBCs by an Antibody. Anti-A
and anti-B have 10 binding sites, located at the 2 tips of each of the 5 Ys,
and can therefore bind multiple RBCs to each other.
Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
Companies, 2003
Chapter 18
Chapter 18 The Circulatory System: Blood 697
ing the risk of a transfusion reaction in certain mismatches,
however, such as giving packed RBCs with a minimum of
plasma.
Contrary to some people’s belief, blood type is not
changed by transfusion. It is fixed at conception and
remains the same for life.
The Rh Group
The Rh blood group is named for the rhesus monkey, in
which the Rh antigens were discovered in 1940. This
group is determined by three genes called C, D, and E,
each of which has two alleles: C, c, D, d, E, e. Whatever

other alleles a person may have, anyone with genotype
DD or Dd has D antigens on his or her RBCs and is classi-
fied as Rh-positive (Rh
ϩ
). In Rh-negative (Rh
Ϫ
) people,
the D antigen is lacking. The Rh blood type is tested by
using an anti-D reagent. The Rh type is usually combined
with the ABO type in a single expression such as O
ϩ
for
type O, Rh-positive, or AB
Ϫ
for type AB, Rh-negative.
About 85% of white Americans are Rh
ϩ
and 15% are Rh
Ϫ
.
ABO blood type has no influence on Rh type, or vice
versa. If the frequency of type O whites in the United
States is 45%, and 85% of these are also Rh
ϩ
, then the fre-
quency of O
ϩ
individuals is the product of these separate
frequencies: 0.45 ϫ 0.85 ϭ 0.38, or 38%. Rh frequencies
vary among ethnic groups just as ABO frequencies do.

About 99% of Asians are Rh
ϩ
, for example.
Think About It
Predict what percentage of Japanese Americans have
type B
Ϫ
blood.
In contrast to the ABO group, anti-D antibodies are not
normally present in the blood. They form only in Rh
Ϫ
indi-
viduals who are exposed to Rh
ϩ
blood. If an Rh
Ϫ
person
receives an Rh
ϩ
transfusion, the recipient produces anti-D.
Since anti-D does not appear instantaneously, this presents
little danger in the first mismatched transfusion. But if that
person should later receive another Rh
ϩ
transfusion, his or
her anti-D could agglutinate the donor’s RBCs.
A related condition sometimes occurs when an Rh
Ϫ
woman carries an Rh
ϩ

fetus. The first pregnancy is likely
to be uneventful because the placenta normally prevents
maternal and fetal blood from mixing. However, at the
time of birth, or if a miscarriage occurs, placental tearing
exposes the mother to Rh
ϩ
fetal blood. She then begins to
produce anti-D antibodies (fig. 18.18). If she becomes preg-
nant again with an Rh
ϩ
fetus, her anti-D antibodies may
pass through the placenta and agglutinate the fetal eryth-
rocytes. Agglutinated RBCs hemolyze, and the baby is
born with a severe anemia called hemolytic disease of the
newborn (HDN), or erythroblastosis fetalis. Not all HDN is
due to Rh incompatibility, however. About 2% of cases
Type A
Type B
Type AB
Type O
Figure 18.16 ABO Blood Typing. Each row shows the
appearance of a drop of blood mixed with anti-A and anti-B antisera.
Blood cells become clumped if they possess the antigens for the
antiserum (top row left, second row right, third row both) but otherwise
remain uniformly mixed. Thus type A agglutinates only in anti-A; type B
agglutinates only in anti-B; type AB agglutinates in both; and type O
agglutinates in neither of them.
Type B
(anti-A)
recipient

Donor RBCs
agglutinated by
recipient plasma
Agglutinated RBCs
block small vessels
Blood from
type A donor
Figure 18.17 Effects of a Mismatched Transfusion. Donor
RBCs become agglutinated in the recipient’s blood plasma. The
agglutinated RBCs lodge in smaller blood vessels downstream from this
point and cut off the blood flow to vital tissues.
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result from incompatibility of ABO and other blood types.
About 1 out of 10 cases of ABO incompatibility between
mother and fetus results in HDN.
HDN, like so many other disorders, is easier to pre-
vent than to treat. If an Rh
Ϫ
woman gives birth to (or mis-
carries) an Rh
ϩ

child, she can be given an Rh immune
globulin (sold under trade names such as RhoGAM and
Gamulin). The immune globulin binds fetal RBC antigens
so they cannot stimulate her immune system to produce
anti-D. It is now common to give immune globulin at 28 to
32 weeks’ gestation and at birth in any pregnancy in which
the mother is Rh
Ϫ
and the father is Rh
ϩ
.
If an Rh
Ϫ
woman has had one or more previous Rh
ϩ
pregnancies, her subsequent Rh
ϩ
children have about a
17% probability of being born with HDN. Infants with
HDN are usually severely anemic. As the fetal hemopoi-
etic tissues respond to the need for more RBCs, erythro-
blasts (immature RBCs) enter the circulation prematurely—
hence the name erythroblastosis fetalis. Hemolyzed RBCs
release hemoglobin, which is converted to bilirubin. High
bilirubin levels can cause kernicterus, a syndrome of toxic
brain damage that may kill the infant or leave it with
motor, sensory, and mental deficiencies. HDN can be treated
with phototherapy—exposing the infant to ultraviolet
light, which degrades bilirubin as blood passes through
the capillaries of the skin. In more severe cases, an

exchange transfusion may be given to completely replace
the infant’s Rh
ϩ
blood with Rh
Ϫ
. In time, the infant’s
hemopoietic tissues will replace the donor’s RBCs with
Rh
ϩ
cells, and by then the mother’s antibody will have dis-
appeared from the infant’s blood.
Think About It
A baby with HDN typically has jaundice and an
enlarged spleen. Explain these effects.
Other Blood Groups
In addition to the ABO and Rh groups, there are at least
100 other known blood groups with a total of more than
500 antigens, including the MN, Duffy, Kell, Kidd, and
Lewis groups. These rarely cause transfusion reactions,
but they are useful for such legal purposes as paternity and
criminal cases and for research in anthropology and pop-
ulation genetics. The Kell, Kidd, and Duffy groups occa-
sionally cause HDN.
698
Part Four Regulation and Maintenance
Uterus
Placenta
(a)
(b) (c)
Amniotic sac

Rh
+
fetus
Rh
–
mother
First pregnancy
Between pregnancies
Second pregnancy
Anti-D
antibodies
Second
Rh
+
fetus
Rh
+
antigens
Figure 18.18 Hemolytic Disease of the Newborn (HDN). (a) When an Rh
Ϫ
woman is pregnant with an Rh
ϩ
fetus, she is exposed to D (Rh)
antigens, especially during childbirth. (b) Following that pregnancy, her immune system produces anti-D antibodies. (c) If she later becomes pregnant
with another Rh
ϩ
fetus, her anti-D antibodies can cross the placenta and agglutinate the blood of that fetus, causing that child to be born with HDN.
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Chapter 18 The Circulatory System: Blood 699
Before You Go On
Answer the following questions to test your understanding of the
preceding section:
18. What are antibodies and antigens? How do they interact to
cause a transfusion reaction?
19. What antibodies and antigens are present in people with each of
the four ABO blood types?
20. Describe the cause, prevention, and treatment of HDN.
21. Why might someone be interested in determining a person’s
blood type other than ABO/Rh?
Leukocytes
Objectives
When you have completed this section, you should be able to
• state the general function that all leukocytes have in common;
• name and describe the five types of leukocytes; and
• describe the types, causes, and effects of abnormal leukocyte
counts.
Leukocytes, or white blood cells (WBCs), play a number of
roles in the body’s defense against pathogens. Their indi-
vidual functions are summarized in table 18.8, but they
are discussed more extensively in chapter 21. There are
five kinds of WBCs. They are easily distinguished from

erythrocytes in stained blood films because they contain
conspicuous nuclei that stain from light violet to dark pur-
ple with the most common blood stains. Three WBC
types—the neutrophils, eosinophils, and basophils—are
called granulocytes because their cytoplasm contains
organelles that appear as colored granules through the
microscope. These are missing or relatively scanty in the
two types known as agranulocytes—the lymphocytes and
monocytes.
Types of Leukocytes
The five leukocyte types are compared in table 18.8. From
the photographs and data, take note of their sizes relative
to each other and to the size of erythrocytes (which are
about 7.5 ␮m in diameter). Also note how the leukocytes
differ from each other in relative abundance—from neu-
trophils, which constitute about two-thirds of the WBC
count, to basophils, which usually account for less than
1%. Nuclear shape is an important key to identifying
leukocytes. The granulocytes are further distinguished
from each other by the coarseness, abundance, and stain-
ing properties of their cytoplasmic granules.
Granulocytes
Neutrophils have very fine cytoplasmic granules that con-
tain lysozyme, peroxidase, and other antibiotic agents.
They are named for the way these granules take up blood
stains at pH 7—some stain with acidic dyes and others
with basic dyes, and the combined effect gives the cyto-
plasm a pale lilac color. The nucleus is usually divided
into three to five lobes, which are connected by strands of
nucleoplasm so delicate that the cell may appear to have

multiple nuclei. Young neutrophils often exhibit an undi-
vided nucleus shaped like a band or a knife puncture; they
are thus called band, or stab, cells. Neutrophils are also
called polymorphonuclear leukocytes (PMNs) because of
their variety of nuclear shapes.
Eosinophils (EE-oh-SIN-oh-fills) are easily distin-
guished by their large rosy to orange-colored granules and
prominent, usually bilobed nucleus.
In basophils, the nucleus is pale and usually hidden
by the coarse, dark violet granules in the cytoplasm. It is
sometimes difficult to distinguish a basophil from a lym-
phocyte, but basophils are conspicuously grainy while the
lymphocyte nucleus is more homogeneous, and basophils
lack the clear blue rim of cytoplasm usually seen in
stained lymphocytes.
Agranulocytes
Lymphocytes are usually similar to erythrocytes in size, or
only slightly larger. They are sometimes classified into
three size classes (table 18.8), but there are gradations
between these categories. Medium and large lymphocytes
are usually seen in fibrous connective tissues and only
occasionally in the circulating blood. In small lympho-
cytes, the nucleus often fills almost the entire cell and
leaves only a narrow rim of clear, light blue cytoplasm.
Large lymphocytes, however, have ample cytoplasm
around the nucleus and are sometimes difficult to distin-
guish from monocytes. There are several subclasses of
lymphocytes with different immune functions (see chap-
ter 21), but they look alike through the light microscope.
Monocytes are the largest of the formed elements,

typically about twice the diameter of an erythrocyte but
sometimes approaching three times as large. The mono-
cyte nucleus tends to stain a lighter blue than most leuko-
cyte nuclei. The cytoplasm is abundant and relatively
clear. In stained blood films monocytes sometimes appear
as very large cells with bizarre stellate (star-shaped) or
polygonal contours (see fig. 18.1a).
Abnormalities of Leukocyte Count
The total WBC count is normally 5,000 to 10,000
WBCs/␮L. A count below this range, called leukopenia
19
(LOO-co-PEE-nee-uh), is seen in lead, arsenic, and mer-
cury poisoning; radiation sickness; and such infectious
19
leuko ϭ white ϩ penia ϭ deficiency
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700 Part Four Regulation and Maintenance
Table 18.8 The White Blood Cells (Leukocytes)
Neutrophils
Percent of WBCs 60%–70%
Mean count 4,150 cells/␮L

Diameter 9–12 ␮m
Appearance*
• Nucleus usually with 3–5 lobes in S- or C-shaped array
• Fine reddish to violet granules in cytoplasm
Differential Count
• Increases in bacterial infections
Functions
• Phagocytosis of bacteria
• Release of antimicrobial chemicals
Eosinophils
Percent of WBCs 2%–4%
Mean count 165 cells/␮L
Diameter 10–14 ␮m
Appearance*
• Nucleus usually has two large lobes connected by thin strand
• Large orange-pink granules in cytoplasm
Differential Count
• Fluctuates greatly from day to night, seasonally, and with phase of menstrual cycle
• Increases in parasitic infections, allergies, collagen diseases, and diseases of spleen and central nervous system
Functions
• Phagocytosis of antigen-antibody complexes, allergens, and inflammatory chemicals
• Release enzymes that weaken or destroy parasites such as worms
Basophils
Percent of WBCs Ͻ 0.5%–1%
Mean count 44 cells/␮L
Diameter 8–10 ␮m
Appearance*
• Nucleus large and U- to S-shaped, but typically pale and obscured from view
• Coarse, abundant, dark violet granules in cytoplasm
Differential Count

• Relatively stable
• Increases in chicken pox, sinusitis, diabetes mellitus, myxedema, and polycythemia
Functions
• Secrete histamine (a vasodilator), which increases blood flow to a tissue
• Secrete heparin (an anticoagulant), which promotes mobility of other WBCs by preventing clotting
Neutrophils
Eosinophil
Basophil
(continued)
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diseases as measles, mumps, chicken pox, poliomyelitis,
influenza, typhoid fever, and AIDS. It can also be pro-
duced by glucocorticoids, anticancer drugs, and immuno-
suppressant drugs given to organ transplant patients.
Since WBCs are protective cells, leukopenia presents an
elevated risk of infection and cancer. A count above
10,000 WBCs/␮L, called leukocytosis,
20
usually indicates
infection, allergy, or other diseases but can also occur in

response to dehydration or emotional disturbances. More
Table 18.8 The White Blood Cells (Leukocytes) (continued)
Lymphocytes
Percent of WBCs 25%–33%
Mean count 2,185 cells/␮L
Diameter
Small class 5–8 ␮m
Medium class 10–12 ␮m
Large class 14–17 ␮m
Appearance*
• Nucleus round, ovoid, or slightly dimpled on one side, of uniform dark violet color
• In small lymphocytes, nucleus fills nearly all of the cell and leaves only a scanty rim of clear, light blue
cytoplasm
• In larger lymphocytes, cytoplasm is more abundant; large lymphocytes may be hard to differentiate from
monocytes
Differential Count
• Increases in diverse infections and immune responses
Functions
• Several functional classes usually indistinguishable by light microscopy
• Destroy cancer cells, cells infected with viruses, and foreign cells
• “Present” antigens to activate other cells of immune system
• Coordinate actions of other immune cells
• Secrete antibodies
• Serve in immune memory
Monocytes
Percent of WBCs 3%–8%
Mean count 456 cells/␮L
Diameter 12–15 ␮m
Appearance*
• Nucleus ovoid, kidney-shaped, or horseshoe-shaped; light violet

• Abundant cytoplasm with sparse, fine granules
• Sometimes very large with stellate or polygonal shapes
Differential Count
• Increases in viral infections and inflammation
Functions
• Differentiate into macrophages (large phagocytic cells of the tissues)
• Phagocytize pathogens, dead neutrophils, and debris of dead cells
• “Present” antigens to activate other cells of immune system
*Appearance pertains to blood films dyed with Wright’s stain.
Lymphocyte
Monocyte
20
leuko ϭ white ϩ cyt ϭ cell ϩ osis ϭ condition
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Chapter 18
useful than a total WBC count is a differential WBC count,
which identifies what percentage of the total WBC count
consists of each type of leukocyte. A high neutrophil
count is a sign of bacterial infection; neutrophils become
sharply elevated in appendicitis, for example. A high
eosinophil count usually indicates an allergy or a parasitic
infection such as hookworms or tapeworms.

Leukemia is a cancer of the hemopoietic tissues that
usually produces an extraordinarily high number of circu-
lating leukocytes and their precursors (fig. 18.19b).
Leukemia is classified as myeloid or lymphoid, acute or
chronic. Myeloid leukemia is marked by uncontrolled
granulocyte production, whereas lymphoid leukemia
involves uncontrolled lymphocyte or monocyte produc-
tion. Acute leukemia appears suddenly, progresses rap-
idly, and causes death within a few months if it is not
treated. Chronic leukemia develops more slowly and may
go undetected for many months; if untreated, the typical
survival time is about 3 years. Both myeloid and lymphoid
leukemia occur in acute and chronic forms. The greatest
success in treatment and cure has been with acute lym-
phoblastic leukemia, the most common type of childhood
cancer. Treatment employs chemotherapy and marrow
transplants along with the control of side effects such as
anemia, hemorrhaging, and infection.
As leukemic cells proliferate, they replace normal
bone marrow and a person suffers from a deficiency of nor-
mal granulocytes, erythrocytes, and platelets. Although
enormous numbers of leukocytes are produced and spill
over into the bloodstream, they are immature cells inca-
pable of performing their normal defensive roles. The defi-
ciency of competent WBCs leaves the patient vulnerable to
opportunistic infection—the establishment of pathogenic
organisms that usually cannot get a foothold in people with
healthy immune systems. The RBC deficiency renders the
patient anemic and fatigued, and the platelet deficiency
results in hemorrhaging and impaired blood clotting. The

immediate cause of death is usually hemorrhage or oppor-
tunistic infection. Cancerous hemopoietic tissue often
metastasizes from the bone marrow or lymph nodes to
other organs of the body, where the cells displace or com-
pete with normal cells. Metastasis to the bone tissue itself
is common and leads to bone and joint pain.
Before You Go On
Answer the following questions to test your understanding of the
preceding section:
22. What is the overall function of leukocytes?
23. What can cause abnormally high or low leukocyte counts?
24. Define leukemia. Distinguish between myeloid and lymphoid
leukemia.
Hemostasis—The Control
of Bleeding
Objectives
When you have completed this section, you should be able to
• describe the body’s mechanisms for controlling bleeding;
• list the functions of platelets;
• describe two reaction pathways that produce blood clots;
• explain what happens to blood clots when they are no longer
needed;
• explain what keeps blood from clotting in the absence of
injury; and
• describe some disorders of blood clotting.
Circulatory systems developed very early in animal evo-
lution, and with them evolved mechanisms for stopping
leaks, which are potentially fatal. Hemostasis
21
is the ces-

702
Part Four Regulation and Maintenance
(b)
Platelets
Neutrophils
Lymphocyte
Erythrocytes
(a)
Monocyte
Figure 18.19 Normal and Leukemic Blood. (a) A normal blood
smear; (b) blood from a patient with acute monocytic leukemia. Note the
abnormally high number of white blood cells, especially monocytes, in b.
With all these extra white cells, why isn’t the body’s infection-
fighting capability increased in leukemia?
21
hemo ϭ blood ϩ stasis ϭ stability
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Chapter 18 The Circulatory System: Blood 703
sation of bleeding. Although hemostatic mechanisms may
not stop a hemorrhage from a large blood vessel, they are
quite effective at closing breaks in small ones. Platelets

play multiple roles in hemostasis, so we begin with a con-
sideration of their form and function.
Platelets
Platelets (see fig. 18.1) are not cells but small fragments of
megakaryocyte cytoplasm. They are 2 to 4 ␮m in diameter
and possess lysosomes, endoplasmic reticulum, a Golgi
complex, and Golgi vesicles, or “granules,” that contain a
variety of factors involved in platelet function. Platelets
have pseudopods and are capable of ameboid movement
and phagocytosis. In normal blood from a fingerstick, the
platelet count ranges from 130,000 to 400,000 platelets/␮L
(averaging about 250,000/␮L). The count can vary greatly,
however, under different physiological conditions and in
blood from different places in the body. When a blood
specimen dries on a slide, platelets clump together; there-
fore in stained blood films, they often appear in clusters.
Platelets have a broad range of functions, many of
which have come to light only in recent years:
• They secrete procoagulants, or clotting factors, which
promote blood clotting.
• They secrete vasoconstrictors, which cause vascular
spasms in broken vessels.
• They form temporary platelet plugs to stop bleeding.
• They dissolve blood clots that have outlasted their
usefulness.
• They phagocytize and destroy bacteria.
• They secrete chemicals that attract neutrophils and
monocytes to sites of inflammation.
• They secrete growth factors that stimulate mitosis in
fibroblasts and smooth muscle and help to maintain

the linings of blood vessels.
There are three hemostatic mechanisms—vascular
spasm, platelet plug formation, and blood clotting (coagula-
tion) (fig. 18.20). Platelets play an important role in all three.
Vascular Spasm
The most immediate protection against blood loss is vas-
cular spasm, a prompt constriction of the broken vessel.
Several things trigger this reaction. An injury stimulates
pain receptors, some of which directly innervate nearby
blood vessels and cause them to constrict. This effect lasts
only a few minutes, but other mechanisms take over by the
time it subsides. Injury to the smooth muscle of the blood
vessel itself causes a longer-lasting vasoconstriction, and
platelets release serotonin, a chemical vasoconstrictor.
Thus, the vascular spasm is maintained long enough for
the other two hemostatic mechanisms to come into play.
Platelet Plug Formation
Platelets will not adhere to the endothelium (inner lining)
of undamaged blood vessels. The endothelium is normally
very smooth and coated with prostacyclin, a platelet
repellent. When a vessel is broken, however, collagen
Vascular spasm
(b) (c)(a)
Platelet plug formation
Blood clotting
Platelet
plug
Vessel injury
Collagen fibers
Endothelial

cells
Platelet
Fibrin
Figure 18.20 Hemostasis. (a) Vasoconstriction of a broken vessel reduces bleeding. (b) A platelet plug forms as platelets adhere to exposed
collagen fibers of the vessel wall. The platelet plug temporarily seals the break. (c) A blood clot forms as platelets and erythrocytes become enmeshed in
fibrin threads. This forms a longer-lasting seal and gives the vessel a chance to repair itself.
How does a clot differ from a platelet plug?
Saladin: Anatomy &
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Chapter 18
fibers of its wall are exposed to the blood. Upon contact
with collagen or other rough surfaces, platelets put out
long spiny pseudopods that adhere to the vessel and to
other platelets; the pseudopods then contract and draw
the walls of the vessel together. The mass of platelets thus
formed, called a platelet plug, may reduce or stop minor
bleeding.
As platelets aggregate, they undergo degranulation—
the exocytosis of their cytoplasmic granules and release of
factors that promote hemostasis. Among these are sero-
tonin, a vasoconstrictor; adenosine diphosphate (ADP),
which attracts more platelets to the area and stimulates
their degranulation; and thromboxane A

2
, an eicosanoid
that promotes platelet aggregation, degranulation, and
vasoconstriction. Thus, a positive feedback cycle is acti-
vated that can quickly seal a small break in a blood vessel.
Coagulation
Coagulation (clotting) of the blood is the last but most
effective defense against bleeding. It is important for the
blood to clot quickly when a vessel has been broken, but
equally important for it not to clot in the absence of vessel
damage. Because of this delicate balance, coagulation is
one of the most complex processes in the body, involving
over 30 chemical reactions. It is presented here in a very
simplified form.
Perhaps clotting is best understood if we first con-
sider its goal. The objective is to convert the plasma pro-
tein fibrinogen into fibrin, a sticky protein that adheres to
the walls of a vessel. As blood cells and platelets arrive,
they become stuck to the fibrin like insects sticking to a
spider web (fig. 18.20). The resulting mass of fibrin, blood
cells, and platelets ideally seals the break in the blood ves-
sel. The complexity of clotting lies in how the fibrin is
formed.
There are two reaction pathways to coagulation
(fig. 18.21). One of them, the extrinsic mechanism, is
initiated by clotting factors released by the damaged blood
vessel and perivascular
22
tissues. The word extrinsic
refers to the fact that these factors come from sources other

than the blood itself. Blood may also clot, however, with-
out these tissue factors—for example, when platelets
adhere to a fatty plaque of atherosclerosis or to a test tube.
The reaction pathway in this case is called the intrinsic
mechanism because it uses only clotting factors found in
the blood itself. In most cases of bleeding, both the extrin-
sic and intrinsic mechanisms work simultaneously to con-
tribute to hemostasis.
Clotting factors (table 18.9) are called procoagulants,
in contrast to the anticoagulants discussed later (see
insight 18.5, p. 708). Most procoagulants are proteins pro-
duced by the liver. They are always present in the plasma
in inactive form, but when one factor is activated, it func-
tions as an enzyme that activates the next one in the path-
way. That factor activates the next, and so on, in a sequence
called a reaction cascade—a series of reactions, each of
which depends on the product of the preceding one. Many
of the clotting factors are identified by Roman numerals,
which indicate the order in which they were discovered,
not the order of the reactions. Factors IV and VI are not
included in table 18.9. These terms were abandoned when
it was found that factor IV was calcium and factor VI was
activated factor V. The last four procoagulants in the table
are called platelet factors (PF
1
through PF
4
) because they
are produced by the platelets.
Initiation of Coagulation

The extrinsic mechanism is diagrammed on the left side of
figure 18.21. The damaged blood vessel and perivascular
tissues release a lipoprotein mixture called tissue throm-
boplastin
23
(factor III). Factor III combines with factor VII
to form a complex which, in the presence of Ca
2ϩ
, then
activates factor X. The extrinsic and intrinsic pathways
differ only in how they arrive at active factor X. Therefore,
before examining their common pathway from factor X to
the end, let’s consider how the intrinsic pathway reaches
this step.
The intrinsic mechanism is diagrammed on the right
side of figure 18.21. Everything needed to initiate it is
present in the plasma or platelets. When platelets degran-
ulate, they release factor XII (Hageman factor, named for
the patient in whom it was discovered). Through a cascade
of reactions, this leads to activated factors XI, IX, and VIII,
in that order—each serving as an enzyme that catalyzes
the next step—and finally to factor X. This pathway also
requires Ca
2ϩ
and PF
3
.
Completion of Coagulation
Once factor X is activated, the remaining events are iden-
tical in the intrinsic and extrinsic mechanisms. Factor X

combines with factors III and V in the presence of Ca
2ϩ
and PF
3
to produce prothrombin activator. This enzyme
acts on a globulin called prothrombin (factor II) and con-
verts it to the enzyme thrombin. Thrombin then chops up
fibrinogen into shorter strands of fibrin. Factor XIII cross-
links these fibrin strands to create a dense aggregation
called fibrin polymer, which forms the structural frame-
work of the blood clot.
Once a clot begins to form, it launches a self-acceler-
ating positive feedback process that seals off the damaged
vessel more quickly. Thrombin works with factor V to
accelerate the production of prothrombin activator, which
in turn produces more thrombin.
704
Part Four Regulation and Maintenance
22
peri ϭ around ϩ vas ϭ vessel ϩ cular ϭ pertaining to
23
thrombo ϭ clot ϩ plast ϭ forming ϩ in ϭ substance
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18. The Circulatory System:
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Chapter 18
Chapter 18 The Circulatory System: Blood 705
The cascade of enzymatic reactions acts as an ampli-
fying mechanism to ensure the rapid clotting of blood (fig.
18.22). Each activated enzyme in the pathway produces a
larger number of enzyme molecules at the following step.
One activated molecule of factor XII at the start of the
intrinsic pathway, for example, causes thousands of fibrin
molecules to be produced very quickly. Note the similar-
ity of this process to the enzyme amplification that occurs
in hormone action (see chapter 17, fig. 17.21).
Notice that the extrinsic mechanism requires fewer
steps to activate factor X than the intrinsic mechanism
does; it is a “shortcut” to coagulation. It takes 3 to 6 min-
utes for a clot to form by the intrinsic pathway but only 15
seconds or so by the extrinsic pathway. For this reason,
when a small wound bleeds, you can stop the bleeding
sooner by massaging the site. This releases thromboplas-
tin from the perivascular tissues and activates or speeds
up the extrinsic pathway.
A number of laboratory tests are used to evaluate the
efficiency of coagulation. Normally, the bleeding of a fin-
gerstick should stop within 2 to 3 minutes, and a sample of
blood in a clean test tube should clot within 15 minutes.
Other techniques are available that can separately assess
the effectiveness of the intrinsic and extrinsic mechanisms.
Extrinsic mechanism Intrinsic mechanism
Factor III
Factor V

Ca
2+
PF
3
Factor V
Factor XIII
Ca
2+
Platelets
Thromboplastin
(factor III)
Factor XII
Damaged
perivascular
tissues
Factor VII
Factor X
Prothrombin
activator
Fibrinogen
(factor I)
Fibrin
Fibrin
polymer
Prothrombin
(factor II)
Thrombin
Factor XI
Factor IX
Factor VIII

Ca
2+
, PF
3
Ca
2+
Figure 18.21 The Pathways of Coagulation. Most clotting factors act as enzymes that convert the next factor from an inactive form (shaded
ellipse) to an active form (lighter ellipse).
Would hemophilia C (see p. 707) affect the extrinsic mechanism, the intrinsic mechanism, or both?
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Chapter 18
The Fate of Blood Clots
After a clot has formed, spinous pseudopods of the
platelets adhere to strands of fibrin and contract. This
pulls on the fibrin threads and draws the edges of the bro-
ken vessel together, like a drawstring closing a purse.
Through this process of clot retraction, the clot becomes
more compact within about 30 minutes.
Platelets and endothelial cells secrete a mitotic stim-
ulant named platelet-derived growth factor (PDGF). PDGF
stimulates fibroblasts and smooth muscle cells to multiply
and repair the damaged blood vessel. Fibroblasts also

invade the clot and produce fibrous connective tissue,
which helps to strengthen and seal the vessel while the
repairs take place.
Eventually, tissue repair is completed and the clot
must be disposed of. Fibrinolysis, the dissolution of a clot,
is achieved by a small cascade of reactions with a positive
feedback component. In addition to promoting clotting,
factor XII catalyzes the formation of a plasma enzyme
called kallikrein (KAL-ih-KREE-in). Kallikrein, in turn,
converts the inactive protein plasminogen into plasmin, a
fibrin-dissolving enzyme that breaks up the clot. Throm-
bin also activates plasmin, and plasmin indirectly pro-
motes the formation of more kallikrein, thus completing a
positive feedback loop (fig. 18.23).
Prevention of Inappropriate
Coagulation
Precise controls are required to prevent coagulation when
it is not needed. These include the following:
• Platelet repulsion. As noted earlier, platelets do not
adhere to the smooth prostacyclin-coated endothelium
of undamaged blood vessels.
706
Part Four Regulation and Maintenance
Table 18.9 Clotting Factors (Procoagulants)
Number Name Origin Function
I Fibrinogen Liver Precursor of fibrin
II Prothrombin Liver Precursor of thrombin
III Tissue thromboplastin Perivascular tissue Activates factor VII
V Proaccelerin Liver Activates factor VII; combines with factor X to form prothrombin
activator

VII Proconvertin Liver Activates factor X in extrinsic pathway
VIII Antihemophiliac factor A Liver Activates factor X in intrinsic pathway
IX Antihemophiliac factor B Liver Activates factor VIII
X Thrombokinase Liver Combines with factor V to form prothrombin activator
XI Antihemophiliac factor C Liver Activates factor IX
XII Hageman factor Liver, platelets Activates factor XI and plasmin; converts prekallikrein to kallikrein
XIII Fibrin-stabilizing factor Platelets, plasma Cross-links fibrin filaments to make fibrin polymer and stabilize
clot
PF
1
Platelet factor 1 Platelets Same role as factor V; also accelerates platelet activation
PF
2
Platelet factor 2 Platelets Accelerates thrombin formation
PF
3
Platelet factor 3 Platelets Aids in activation of factor VIII and prothrombin activator
PF
4
Platelet factor 4 Platelets Binds heparin during clotting to inhibit its anticoagulant effect
Factor XII
Factor XI
Factor IX
Factor VIII
Factor X
Prothrombin activator
Thrombin
Fibrin
Reaction cascade
Figure 18.22 Enzyme Amplification in Blood Clotting. Each

clotting factor produces many molecules of the next one, so the number
of active clotting factors increases rapidly and a large amount of fibrin is
quickly formed. The example shown here is for the intrinsic mechanism.
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Blood
Text
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Chapter 18
Chapter 18 The Circulatory System: Blood 707
• Dilution. Small amounts of thrombin form
spontaneously in the plasma, but at normal rates of
blood flow the thrombin is diluted so quickly that a
clot has little chance to form. If flow decreases,
however, enough thrombin can accumulate to cause
clotting. This can happen in circulatory shock, for
example, when output from the heart is diminished
and circulation slows down.
• Anticoagulants. Thrombin formation is suppressed by
anticoagulants that are present in the plasma.
Antithrombin, secreted by the liver, deactivates
thrombin before it can act on fibrinogen. Heparin,
secreted by basophils and mast cells, interferes with
the formation of prothrombin activator, blocks the
action of thrombin on fibrinogen, and promotes the
action of antithrombin. Heparin is given by injection

to patients with abnormal clotting tendencies.
Coagulation Disorders
In a process as complex as coagulation, it is not surprising
that things can go wrong. Clotting deficiencies can result
from causes as diverse as malnutrition, leukemia, and gall-
stones (see insight 18.4).
A deficiency of any clotting factor can shut down the
coagulation cascade. This happens in hemophilia, a family
of hereditary diseases characterized by deficiencies of one
factor or another. Because of its sex-linked recessive mech-
anism of heredity, most hemophilia occurs predominantly
in males. They can inherit it only from their mothers, how-
ever, as happened with the descendants of Queen Victoria.
The lack of factor VIII causes classical hemophilia (hemo-
philia A), which accounts for about 83% of cases and
afflicts 1 in 5,000 males worldwide. Lack of factor IX causes
hemophilia B, which accounts for 15% of cases and occurs
in about 1 out of 30,000 males. Factors VIII and IX are there-
fore known as antihemophilic factors A and B. A rarer form
called hemophilia C (factor XI deficiency) is autosomal, not
sex-linked, so it occurs equally in both sexes.
Before purified factor VIII became available in the
1960s, more than half of those with hemophilia died before
age 5 and only 10% lived to age 21. Physical exertion causes
bleeding into the muscles and joints. Excruciating pain and
eventual joint immobility can result from intramuscular and
joint hematomas
24
(masses of clotted blood in the tissues).
Hemophilia varies in severity, however. Half of the normal

level of clotting factor is enough to prevent the symptoms,
and the symptoms are mild even in individuals with as little
as 30% of the normal amount. Such cases may go undetected
even into adulthood. Bleeding can be relieved for a few days
by transfusion of plasma or purified clotting factors.
Think About It
Why is it important for people with hemophilia not to
use aspirin? (Hint: See p. 666.)
Insight 18.4 Clinical Application
Liver Disease and Blood Clotting
Proper blood clotting depends on normal liver function for two rea-
sons. First, the liver synthesizes most of the clotting factors. Therefore,
diseases such as hepatitis, cirrhosis, and cancer that degrade liver func-
tion result in a deficiency of clotting factors. Second, the synthesis of
clotting factors II, VII, IX, and X require vitamin K. The absorption of
vitamin K from the diet requires bile, a liver secretion. Gallstones can
lead to a clotting deficiency by obstructing the bile duct and thus
interfering with bile secretion and vitamin K absorption. Efficient
blood clotting is especially important in childbirth, since both the
mother and infant bleed from the trauma of birth. Therefore, pregnant
women should take vitamin K supplements to ensure fast clotting, and
newborn infants may be given vitamin K injections.
Far more people die from unwanted blood clotting
than from clotting failure. Most strokes and heart attacks are
due to thrombosis—the abnormal clotting of blood in an
unbroken vessel. A thrombus (clot) may grow large enough
to obstruct a small vessel, or a piece of it may break loose
and begin to travel in the bloodstream as an embolus.
25
An

embolus may lodge in a small artery and block blood flow
Prekallikrein
Kallikrein
Plasminogen
Fibrin
polymer
Positive
feedback
loop
Clot dissolution
Fibrin degradation
products
Factor XII
Plasmin
Figure 18.23 The Mechanism for Dissolving Blood Clots.
Prekallikrein is converted to kallikrein. Kallikrein is an enzyme that
catalyzes the formation of plasmin. Plasmin is an enzyme that dissolves
the blood clot.
24
hemat ϭ blood ϩ oma ϭ mass
25
em ϭ in, within ϩ bolus ϭ ball, mass
Saladin: Anatomy &
Physiology: The Unity of
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Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill

Companies, 2003
Chapter 18
from that point on. If that vessel supplies a vital organ such
as the heart, brain, lung, or kidney, infarction (tissue death)
may result. About 650,000 Americans die annually of
thromboembolism (traveling blood clots) in the cerebral,
coronary, and pulmonary arteries.
Thrombosis is more likely to occur in veins than in
arteries because blood flows more slowly in the veins and
does not dilute thrombin and fibrin as rapidly. It is espe-
cially common in the leg veins of inactive people and
patients immobilized in a wheelchair or bed. Most venous
blood flows directly to the heart and then to the lungs.
Therefore, blood clots arising in the legs or arms com-
monly lodge in the lungs and cause pulmonary embolism.
When blood cannot circulate freely through the lungs, it
cannot receive oxygen and a person may die of hypoxia.
Table 18.10 describes some additional disorders of
the blood. The effects of aging on the blood are described
on pages 1110 to 1111.
Before You Go On
Answer the following questions to test your understanding of the
preceding section:
25. What are the three basic mechanisms of hemostasis?
26. How do the extrinsic and intrinsic mechanisms of coagulation
differ? What do they have in common?
27. In what respect does blood clotting represent a negative
feedback loop? What part of it is a positive feedback loop?
28. Describe some of the mechanisms that prevent clotting in
undamaged vessels.

29. Describe a common source and effect of pulmonary embolism.
Insight 18.5 Clinical Application
Controlling Coagulation
For many cardiovascular patients, the goal of treatment is to prevent
clotting or to dissolve clots that have already formed. Several strate-
gies employ inorganic salts and products of bacteria, plants, and ani-
mals with anticoagulant and clot-dissolving effects.
Preventing Clots from Forming
Since calcium is an essential requirement for blood clotting, blood sam-
ples can be kept from clotting by adding a few crystals of sodium
oxalate, sodium citrate, or EDTA
26
—salts that bind calcium ions and pre-
vent them from participating in the coagulation reactions. Blood-
collection equipment such as hematocrit tubes may also be coated with
heparin, a natural anticoagulant whose action was explained earlier.
Since vitamin K is required for the synthesis of clotting factors, any-
thing that antagonizes vitamin K usage makes the blood clot less read-
ily. One vitamin K antagonist is coumarin
27
(COO-muh-rin), a sweet-
smelling extract of tonka beans, sweet clover, and other plants, used in
perfume. Taken orally by patients at risk for thrombosis, coumarin
takes up to 2 days to act, but it has longer-lasting effects than heparin.
A similar vitamin K antagonist is the pharmaceutical preparation War-
farin
28
(Coumadin), which was originally developed as a pesticide—it
makes rats bleed to death. Obviously, such anticoagulants must be used
in humans with great care.

As explained in chapter 17, aspirin suppresses the formation of
prostaglandins including thromboxane A
2
, a factor in platelet aggre-
gation. Low daily doses of aspirin can therefore suppress thrombosis
and prevent heart attacks.
Many parasites feed on the blood of vertebrates and secrete anti-
coagulants to keep the blood flowing. Among these are segmented
708 Part Four Regulation and Maintenance
Table 18.10 Some Disorders of the Blood
Infectious mononucleosis Infection of B lymphocytes with Epstein-Barr virus, most commonly in adolescents and young adults. Usually
transmitted by exchange of saliva, as in kissing. Causes fever, fatigue, sore throat, inflamed lymph nodes, and
leukocytosis. Usually self-limiting and resolves within a few weeks.
Thalassemia A group of hereditary anemias most common in Greeks, Italians, and others of Mediterranean descent; shows a
deficiency or absence of ␣ or ␤ hemoglobin and RBC counts that may be less than 2 million/␮L.
Thrombocytopenia A platelet count below 100,000/␮L. Causes include bone marrow destruction by radiation, drugs, poisons, or leukemia.
Signs include small hemorrhagic spots in the skin or hematomas in response to minor trauma.
Disseminated intravascular Widespread clotting within unbroken vessels, limited to one organ or occurring throughout the body. Usually triggered
coagulation (DIC) by septicemia but also occurs when blood circulation slows markedly (as in cardiac arrest). Marked by widespread
hemorrhaging, congestion of the vessels with clotted blood, and tissue necrosis in blood-deprived organs.
Septicemia Bacteremia (bacteria in the bloodstream) accompanying infection elsewhere in the body. Often causes fever, chills,
and nausea, and may cause DIC or septic shock. (see p. 765)
Disorders described elsewhere
Anemia 692 Hypoproteinemia 682 Polycythemia 692
Embolism 708 Hypoxemia 685 Sickle-cell disease 693
Hematoma 198, 707 Leukemia 702 Thrombosis 707
Hemolytic disease of the newborn 697 Leukocytosis 701 Transfusion reaction 696
Hemophilia 707 Leukopenia 699
Saladin: Anatomy &
Physiology: The Unity of

Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
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Chapter 18
Chapter 18 The Circulatory System: Blood 709
worms known as leeches. Leeches secrete a local anesthetic that makes
their bites painless; therefore, as early as 1567
B
.
C
.
E
., physicians used
them for bloodletting. This method was less painful and repugnant to
their patients than phlebotomy
29
—cutting a vein—and indeed, leech-
ing became very popular. In seventeenth-century France it was quite
the rage; tremendous numbers of leeches were used to treat
headaches, insomnia, whooping cough, obesity, tumors, menstrual
cramps, mental illness, and almost anything else doctors or their
patients imagined to be caused by “bad blood.”
The first known anticoagulant was discovered in the saliva of the
medicinal leech, Hirudo medicinalis, in 1884. Named hirudin, it is a
polypeptide that prevents clotting by inhibiting thrombin. It causes the
blood to flow freely while the leech feeds and for as long as an hour

thereafter. While the doctrine of bad blood is now discredited, leeches
have lately reentered medical usage (fig. 18.24). A major problem in
reattaching a severed body part such as a finger or ear is that the tiny
veins draining these organs are too small to reattach surgically. Since
arterial blood flows into the reattached organ and cannot flow out, it
pools and clots there. This inhibits the regrowth of veins and the flow
of fresh blood through the organ and thus often leads to necrosis.
Some vascular surgeons now place leeches on the reattached part.
Their anticoagulant keeps the blood flowing freely and allows new
veins to grow. After 5 to 7 days, venous drainage is restored and leech-
ing can be stopped.
Anticoagulants also occur in the venom of some snakes. Arvin,
for example, is obtained from the venom of the Malayan viper. It
rapidly breaks down fibrinogen and may have potential as a clinical
anticoagulant.
Dissolving Clots That Have Already Formed
When a clot has already formed, it can be treated with clot-dissolving
drugs such as streptokinase, an enzyme made by certain bacteria
(streptococci). Intravenous streptokinase is used to dissolve blood clots
in coronary vessels, for example. It is nonspecific, however, and digests
almost any protein. Tissue plasminogen activator (TPA) works faster, is
more specific, and is now made by transgenic bacteria. TPA converts
plasminogen into the clot-dissolving enzyme plasmin. Some anticoag-
ulants of animal origin also work by dissolving fibrin. A giant Amazon
leech, Haementeria, produces one such anticoagulant named
hementin. This, too, has been successfully produced by genetically
engineered bacteria and used to dissolve blood clots in cardiac
patients.
26
ethylenediaminetetraacetic acid

27
coumarú, tonka bean tree
28
acronym from Wisconsin Alumni Research Foundation
29
phlebo ϭ vein ϩ tomy ϭ cutting
Figure 18.24 A Modern Use of Leeching. Two medicinal leeches
are being used to remove clotted blood from a postsurgical hematoma.
These leeches grow up to 20 cm long.
Functions and Properties of Blood
(p. 680)
1. Blood serves to transport O
2
, CO
2
,
nutrients, wastes, hormones, and
heat; it protects the body by means of
antibodies, leukocytes, platelets, and
its roles in inflammation; and it helps
to stabilize the body’s water balance
and fluid pH.
2. Blood is about 55% plasma and 45%
formed elements by volume.
3. The formed elements include
erythrocytes, platelets, and five kinds
of leukocytes.
4. The viscosity of blood, stemming
mainly from its RBCs and proteins, is
an important factor in blood flow.

5. The osmolarity of blood, stemming
mainly from its RBCs, proteins, and
Na
ϩ
, governs its water content and is
thus a major factor in blood volume
and pressure. The protein
contribution to osmolarity is the
colloid osmotic pressure.
Plasma (p. 683)
1. Protein is the most abundant plasma
solute by weight. The three major
plasma proteins are albumins,
globulins, and fibrinogen.
2. The liver produces all the plasma
proteins except ␥ globulins
(antibodies), which are produced by
plasma cells.
3. Nonprotein nitrogenous substances in
the plasma include amino acids and
nitrogenous wastes. The most
abundant nitrogenous waste is urea.
4. Nutrients carried in the plasma
include glucose, amino acids, fats,
cholesterol, phospholipids, vitamins,
and minerals.
Chapter Review
Review of Key Concepts
Saladin: Anatomy &
Physiology: The Unity of

Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
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Chapter 18
710 Part Four Regulation and Maintenance
5. Plasma electrolytes include several
inorganic salts (table 18.3); the most
abundant cation is Na
ϩ
.
Blood Cell Production (p. 684)
1. Hemopoiesis is the production of the
formed elements of blood. It begins in
the embryonic yolk sac and continues
in the fetal bone marrow, liver,
spleen, and thymus. From infancy
onward, it occurs in the bone marrow
(myeloid hemopoiesis) and lymphoid
tissues (lymphoid hemopoiesis).
2. Myeloid hemopoiesis begins with
pluripotent stem cells called
hemocytoblasts. Some of their
daughter cells differentiate into
committed cells, which have
receptors for various stimulatory
chemicals and are destined to

develop into one specific type or
group of formed elements.
3. Erythropoiesis, the production of
RBCs, is stimulated by the hormone
erythropoietin. It is regulated by a
negative feedback loop that responds
to hypoxemia with increased EPO
secretion, and thus increased
erythropoiesis.
4. Iron, in the form of ferrous ions
(Fe
2ϩ
), is essential for hemoglobin
synthesis and erythropoiesis, as well
as synthesis of myoglobin and
mitochondrial cytochromes. Dietary
Fe
3ϩ
is converted to Fe
2ϩ
by stomach
acid, then binds to gastroferritin, is
absorbed into the blood, and binds
with the plasma protein transferrin.
Transferrin transports Fe
2ϩ
to the
myeloid tissue and liver. The liver
stores excess iron in ferritin.
5. Leukopoiesis, the production of WBCs,

follows three lines starting with B and
T progenitor cells (which become B
and T lymphocytes) and granulocyte-
macrophage colony-forming units
(which become granulocytes and
monocytes). These committed cells
develop into mature WBCs under the
influence of colony-stimulating factors.
6. Circulating WBCs remain in the
bloodstream for only a matter of
hours, and spend most of their lives
in other tissues. Lymphocytes cycle
repeatedly from blood to tissue fluids
to lymph and back to the blood.
7. Thrombopoiesis, the production of
platelets, is stimulated by
thrombopoietin. This hormone
induces the formation of large cells
called megakaryocytes, which pinch
off bits of peripheral cytoplasm that
break up into platelets.
Erythrocytes (p. 689)
1. RBCs serve to transport O
2
and CO
2
.
They are discoid cells with a sunken
center and no organelles, but they do
have a cytoskeleton of spectrin and

actin that reinforces the plasma
membrane.
2. The most important components of
the cytoplasm are hemoglobin (Hb)
and carbonic anhydrase (CAH). Hb
transports nearly all of the O
2
and
some of the CO
2
in the blood, and
CAH catalyzes the reversible reaction
CO
2
ϩ H
2
O ↔ H
2
CO
3
.
3. Hb consists of four proteins—two ␣
and two ␤ chains—each with a heme
moiety.
4. Oxygen binds to the Fe
2ϩ
at the
center of each heme. About 5% of the
CO
2

in the blood binds to the globin
moiety for transport.
5. Hemoblogin occurs in forms HbA
(adult hemoglobin), HbA
2
, and HbF
(fetal hemoglobin), which differ in
amino acid composition and oxygen-
binding properties.
6. The quantities of RBCs and Hb are
clinically important. They are
measured in terms of hematocrit
(percent of the blood volume
composed of RBCs), hemoglobin
concentration (g/dL), and RBC count
(RBCs/␮L of blood). Normal
averages are lower in women than
in men.
7. An RBC lives for about 120 days,
grows increasingly fragile, and then
breaks apart, especially in the spleen.
Hemolysis, the rupture of RBCs,
releases cell fragmens and free Hb.
8. Hb is broken down into its globin and
heme moieties. The globin is
hydrolyzed into its free amino acids,
which are reused. The heme is broken
down into its Fe
2ϩ
and organic

components. The Fe
2ϩ
is recycled or
stored, and the organic component
eventually becomes biliverdin and
bilirubin (bile pigments), which are
excreted as waste.
9. An excessive RBC count is
polycythemia. Primary polycythemia
results from cancer of the bone
marrow, and secondary polycythemia
from many other causes, such as
dehydration, smoking, high altitude,
and habitual strenuous exercise.
Polycythemia increases blood
volume, pressure, and viscosity to
sometimes dangerous levels.
10. A deficiency of RBCs is anemia.
Anemia can result from inadequate
erythropoiesis, hemorrhage, or
hemolysis.
11. Causes of anemia are classified and
described in table 18.6.
12. The effects of anemia include tissue
hypoxia and necrosis, reduced blood
osmolarity, and reduced blood
viscosity.
13. Sickle-cell disease and thalassemia
are hereditary hemoglobin defects
that result in severe anemia and

multiple other effects.
Blood Types (p. 694)
1. Blood types are determined by
antigenic glycoproteins and
glycolipids on the RBC surface.
Incompatibility of one person’s blood
with another results from the action
of plasma antibodies against these
RBC antigens.
2. Blood types A, B, AB, and O form the
ABO blood group. The first two have
antigen A or B on the RBC surface,
the third has both A and B, and type
O has neither.
3. A few months after birth, a person
develops anti-A and anti-B antibodies
against intestinal bacteria. These
antibodies cross-react with foreign
ABO antigens and thus limit
transfusion compatibility.
4. When anti-A reacts with type A or
AB red cells, or anti-B reacts with
type B or AB red cells, the red cells
agglutinate and hemolyze, causing a
severe transfusion reaction that can
lead to renal failure and death.
5. The Rh blood group is inherited
through genes called C, D, and E.
Anyone with genotype DD or Dd is
Rh-positive (Rh

ϩ
).
6. An Rh-negative (Rh
Ϫ
) person who is
exposed to Rh
ϩ
RBCs through
transfusion or childbirth develops an
anti-D antibody. Later exposures to
Rh
ϩ
red cells can cause a transfusion
reaction.
7. Rh incompatibility between a
sensitized Rh
Ϫ
woman and an Rh
ϩ
fetus can cause hemolytic disease of
the newborn, a severe neonatal
anemia that must be treated by
phototherapy or transfusion.
8. Many other blood groups besides
ABO and Rh exist. They rarely cause
transfusion reactions but are useful in
Saladin: Anatomy &
Physiology: The Unity of
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Edition

18. The Circulatory System:
Blood
Text
© The McGraw−Hill
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Chapter 18
Chapter 18 The Circulatory System: Blood 711
paternity and criminal cases and for
studies of population genetics.
Leukocytes (p. 699)
1. WBCs play various roles in defending
the body from pathogens. Neutrophils,
eosinophils, and basophils are
classified as granulocytes while
lymphocytes and monocytes are
classified as agranulocytes. The
appearance and function of each type
are detailed in table 18.8.
2. A WBC deficiency, called leukopenia,
may result from chemical or radiation
poisoning, various infections, and
certain drugs. It reduces a person’s
resistance to infection and cancer.
3. A WBC excess, called leukocytosis,
may result from infection, allergy,
dehydration, or emotional disorders,
or from leukemia (cancer of the
hemopoietic tissues).
4. Leukemia is classified by site of
origin as myeloid or lymphoid, and

by speed of progression as acute or
chronic. Leukemia increases the risk
of opportunistic infection and is
typically accompanied by RBC and
platelet deficiencies.
Hemostasis—The Control of Bleeding
(p. 702)
1. Platelets are not cells but small,
mobile, phagocytic fragments of
megakaryocyte cytoplasm, second
only to RBCs in abundance.
2. Platelets contribute to hemostasis
(cessation of bleeding) by secreting
procoagulants and vasoconstrictors
and plugging small broken blood
vessels. They also help to dissolve
clots that are no longer needed,
phagocytize bacteria, attract
neutrophils and monocytes to
inflamed tissues, and secrete growth
factors that maintain blood vessels
and promote tissue repair.
3. Breakage of a blood vessel leads first
to vascular spasm, then formation of
a platelet plug, and third but most
effectively, coagulation (formation of
a blood clot).
4. The objective of coagulation is to
form a mesh of sticky protein called
fibrin. There are two biochemical

pathways to fibrin production, called
the extrinsic and intrinsic
mechanisms. Both pathways involve
a self-amplifying chain reaction, or
reaction cascade, of chemicals called
procoagulants.
5. The extrinsic mechanism depends on
chemicals released by damaged cells
outside the bloodstream. It begins with
release of a lipoprotein called tissue
thromboplastin and leads to activation
of a procoagulant called factor X.
6. The intrinsic mechanism employs
only factors found in the blood
plasma or platelets. It begins with
factor XII and likewise ends with the
activation of factor X.
7. Beyond the activation of factor X,
events are identical regardless of
intrinsic or extrinsic beginnings. The
remaining steps include activation of
the enzyme thrombin, which cuts
plasma fibrinogen into fibrin. Fibrin
then polymerizes to form the weblike
matrix of the blood clot.
8. Positive feedback and enzyme
amplification ensure rapid clotting
and the production of a large amount
of fibrin in spite of small amounts of
the other procoagulants that drive the

process.
9. After a clot forms, it exhibits a
consolidation process called clot
retraction that helps to seal the
wound. Platelet-derived growth factor
promotes repair of the damaged blood
vessel and surrounding connective
tissues. Tissue repair is followed by
fibrinolysis, in which the blood clot,
no longer needed, is dissolved by the
enzyme plasmin.
10. Inappropriate coagulation is normally
prevented by the repulsion of
platelets by prostacyclin on the blood
vessel endothelium, dilution of the
small amounts of thrombin that form
spontaneously, and anticoagulants
such as heparin.
11. Clotting deficiency can result from
thrombocytopenia (low platelet count)
or hemophilia (hereditary deficiency
in procoagulant structure and
function, especially in factor VIII).
12. Unwanted clotting in unbroken blood
vessels is called thrombosis. A
thrombus (clot) can break loose and
become a traveling embolus, which
can cause sometimes fatal obstruction
of small blood vessels.
Selected Vocabulary

hematology 680
plasma 680
erythrocyte 680
platelet 680
leukocyte 680
granulocyte 680
neutrophil 680
eosinophil 680
basophil 680
agranulocyte 680
lymphocyte 680
monocyte 680
colloid osmotic pressure 682
albumin 683
globulin 683
fibrinogen 683
hemopoiesis 685
hypoxemia 685
hemoglobin 689
hematocrit 691
polycythemia 692
anemia 692
ABO blood group 695
agglutination 696
Rh blood group 697
leukopenia 699
leukocytosis 701
leukemia 702
hemostasis 702
coagulation 704

fibrin 704
prothrombin 704
hematoma 707
thrombosis 707
embolus 707
Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
Companies, 2003
Chapter 18
712 Part Four Regulation and Maintenance
Testing Your Recall
1. Antibodies belong to a class of
plasma proteins called
a. albumins.
b. ␥ globulins.
c. ␣ globulins.
d. procoagulants.
e. agglutinins.
2. Serum is blood plasma minus its
a. sodium ions.
b. calcium ions.
c. clotting proteins.
d. globulins.
e. albumins.

3. Which of the following conditions is
most likely to cause hemolytic
anemia?
a. folic acid deficiency
b. iron deficiency
c. mushroom poisoning
d. alcoholism
e. hypoxemia
4. It is impossible for a type O
ϩ
baby to
have a type ______ mother.
a. AB
Ϫ
b. O
Ϫ
c. O
ϩ
d. A
ϩ
e. B
ϩ
5. Which of the following is not a
component of hemostasis?
a. platelet plug formation
b. agglutination
c. clot retraction
d. a vascular spasm
e. degranulation
6. Which of the following contributes

most to the viscosity of blood?
a. albumin
b. sodium
c. globulins
d. erythrocytes
e. fibrin
7. Which of these is a granulocyte?
a. a monocyte
b. a lymphocyte
c. a macrophage
d. an eosinophil
e. an erythrocyte
8. Excess iron is stored in the liver as a
complex called
a. gastroferritin.
b. transferrin.
c. ferritin.
d. hepatoferritin.
e. erythropoietin.
9. Pernicious anemia is a result of
a. hypoxemia.
b. iron deficiency.
c. malaria.
d. lack of intrinsic factor.
e. Rh incompatibility.
10. The first clotting factor that the
intrinsic and extrinsic pathways have
in common is
a. thromboplastin.
b. Hageman factor.

c. factor X.
d. prothrombin activator.
e. factor VIII.
11. Production of all the formed elements
of blood is called ______.
12. The percentage of blood volume
composed of RBCs is called the
______.
13. The extrinsic pathway of coagulation
is activated by ______ from damaged
perivascular tissues.
14. The RBC antigens that determine
transfusion compatibility are called
______.
15. The hereditary lack of factor VIII
causes a disease called ______.
16. The overall cessation of bleeding,
involving several mechanisms, is
called ______.
17. ______ results from a mutation that
changes one amino acid in the
hemoglobin molecule.
18. An excessively high RBC count is
called ______.
19. Intrinsic factor enables the small
intestine to absorb ______.
20. The kidney hormone ______
stimulates RBC production.
Answers in Appendix B
Answers in Appendix B

True or False
Determine which five of the following
statements are false, and briefly
explain why.
1. By volume, the blood usually
contains more plasma than blood
cells.
2. An increase in the albumin
concentration of the blood would
tend to increase blood pressure.
3. Anemia is caused by a low oxygen
concentration in the blood.
4. Hemostasis, coagulation, and clotting
are three terms for the same process.
5. A man with blood type A
ϩ
and a
woman with blood type B
ϩ
could
have a baby with type O
Ϫ
.
6. Lymphocytes are the most abundant
WBCs in the blood.
7. Calcium ions are required for blood
clotting.
8. All formed elements of the blood
come ultimately from
hemocytoblasts.

9. When RBCs die and break down, the
globin moiety of hemoglobin is
excreted and the heme is recycled to
new RBCs.
10. Leukemia is a severe deficiency of
white blood cells.
Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
18. The Circulatory System:
Blood
Text
© The McGraw−Hill
Companies, 2003
Chapter 18
Chapter 18 The Circulatory System: Blood 713
Testing Your Comprehension
1. Why would erythropoiesis not correct
the hypoxemia resulting from lung
cancer?
2. People with chronic kidney disease
often have hematocrits of less than
half the normal value. Explain why.
3. An elderly white woman is hit by a
bus and severely injured. Accident
investigators are informed that she
lives in an abandoned warehouse,
where her few personal effects
include several empty wine bottles

and an expired driver’s license
indicating she is 72 years old. At the
hospital, she is found to be severely
anemic. List all the factors you can
think of that may contribute to her
anemia.
4. How is coagulation different from
agglutination?
5. Although fibrinogen and prothrombin
are equally necessary for blood
clotting, fibrinogen is about 4% of the
plasma protein while prothrombin is
present only in small traces. In light
of the roles of these clotting factors
and your knowledge of enzymes,
explain this difference in their
abundance.
Answers at the Online Learning Center
Answers to Figure Legend Questions
18.1 A nucleus
18.9 About 1.3 times the diameter of an
RBC, therefore about 10 ␮m
18.19 Although numerous, these WBCs
are immature and incapable of
performing their defensive roles.
18.20 A platelet plug lacks the fibrin
mesh that a blood clot has.
18.21 It would affect only the intrinsic
mechanism.
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Saladin: Anatomy &
Physiology: The Unity of
Form and Function, Third
Edition
19. The Circulatory System:
The Heart
Text
© The McGraw−Hill
Companies, 2003
Gross Anatomy of the Heart 716
• Overview of the Cardiovascular System 716
• Size, Shape, and Position of the Heart 717
• The Pericardium 718
• The Heart Wall 718
• The Chambers 720
• The Valves 721
• Blood Flow Through the Heart 724
• The Coronary Circulation 724
Cardiac Muscle and the Cardiac Conduction
System 726
• Structure of Cardiac Muscle 726
• Metabolism of Cardiac Muscle 727
• The Cardiac Conduction System 727
Electrical and Contractile Activity of
the Heart 728
• The Cardiac Rhythm 728
• Physiology of the SA Node 728

• Impulse Conduction to the Myocardium 728
• Electrical Behavior of the Myocardium 729
• The Electrocardiogram 730
Blood Flow, Heart Sounds, and the Cardiac
Cycle 733
• Principles of Pressure and Flow 733
• Heart Sounds 734
• Phases of the Cardiac Cycle 734
• Overview of Volume Changes 736
Cardiac Output 737
• Heart Rate 738
• Stroke Volume 739
• Exercise and Cardiac Output 740
Chapter Review 743
INSIGHTS
19.1 Clinical Application: Valvular
Insufficiency 723
19.2 Clinical Application: Myocardial
Infarction and Angina Pectoris 725
19.3 Clinical Application: Cardiac
Arrhythmias 732
19.4 Clinical Application: Congestive
Heart Failure 737
19.5 Clinical Application: Coronary
Atherosclerosis 741
19
CHAPTER
The Circulatory
System: The Heart
A semilunar valve of the heart (endoscopic photo)

CHAPTER OUTLINE
Brushing Up
To understand this chapter, it is important that you understand or
brush up on the following concepts:
• Properties of cardiac muscle (pp. 176, 432)
• Desmosomes and gap junctions (p. 179)
• Ultrastructure of striated muscle (pp. 409–411)
• Excitation-contraction coupling in muscle (p. 417)
• Length-tension relationship in muscle fibers (p. 422)
• Action potentials (p. 458)
715